Depression is among the most disabling human illnesses worldwide, and current treatments fall short of what is required to meet this large public health need. Anhedonia ? the markedly diminished response to pleasure ? is a core feature of depression and is linked to impaired psychosocial functioning, poor treatment outcome, suicidal behavior and often persists despite treatment with a serotonin selective reuptake inhibitor. Increased signaling of pro-inflammatory cytokines, including interleukin 6 (IL-6), lead to anhedonic behavior in animals, patients with depression are characterized by elevated levels of IL-6 and other cytokines, and administration of pro-inflammatory cytokines triggers depressive symptoms and changes in brain responses to reward in human subjects. Despite these data, there is significant heterogeneity in the literature and it is now clear that there is not a one-to-one mapping of pro-inflammatory cytokines to depressive symptoms. The current proposal seeks to go beyond linking inflammation to depressive phenotypes by testing the relationships between peripheral inflammatory factors and neural and behavioral responses to reward and social stimuli in patients with anhedonia across a range of depressive disorders. The proposal leverages state-of-the-art immunological techniques to examine inflammatory response profiles of leukocytes harvested from patients and stimulated ex vivo. Our goal is to characterize meaningful immune-brain-behavior profiles underlying the phenotype of anhedonia in humans in order to promote novel diagnostic and treatment development efforts. We will confirm and expand on our previous published finding of elevated basal levels of IL-6 in patients with major depressive disorder (MDD) by examining IL-6 augmented with a board panel of cytokines in patients enriched for anhedonia across a spectrum of depression in both un-stimulated (basal) and stimulated conditions (Aim 1). Building on the peripheral immune profiles developed in Aim 1, we will use quantitative computer-based assessments of reward learning [probabilistic reward task (PRT)] and functional magnetic resonance imaging (fMRI) with monetary incentive [incentive flanker task (IFT)] and positive social emotion [positive faces task (PFT) 10] tasks to develop immune-brain-behavior multimodal profiles of anhedonia (Aim 2). Supporting these aims, our pilot work show that (a) high IL-6 is linked to poor reward learning, (b) high IL-6 is linked to reduced response to positive emotion within the rostral anterior cingluate cortex (rACC), and (c) high IL-6 is linked to reduced response to monetary incentives (reward outcome) within the ventromedial prefrontal cortex (vmPFC). Our project has the potential to have a major public health impact by developing multimodal immune-brain- behavior profiles in order to advance novel diagnostic and treatment development.